Abstract:

Background: The growth hormone (GH) and insulin-like growth factor-1 (IGF-1) axis is a major regulator of mammalian growth. In humans, two GH genes encode two GH proteins: pituitary GH (GH-N) and GH-V variant (GH-V). GH-V is thought to play a key role in maternal adaptation to pregnancy. However, to date, the exact function of GH-V during pregnancy is poorly understood. Aim: The primary aim of the work detailed in this thesis was to identify the effect of GH-V on pregnancy outcomes, in terms of fetal growth and maternal metabolism, in experimental animal models and to determine whether circulating GH-V was altered in a human cohort with well characterized pregnancy outcomes. Methods: 1) Literature review: In order to determine the gap in research knowledge, Pubmed, Medline and CINAHL databases were searched for literature related to placental development, and potential roles of GH in normal and pathological pregnancies. 2) An animal study was conducted to determine the dose-response relationship for human GH-V treatment in a mouse model of normal pregnancy. Following time-mating, pregnant wild-type C57BL/6J mice were randomized to receive different doses of GH-V treatment (0.25, 1, 2, 5 mg/kg per day) or vehicle control from gestational day 12.5 to 18.5 via osmotic pump. 3) Daily versus continuous administration of GH-V was compared in non-pregnant mice to determine the effect of GH-V on mice via different modes of administration. C57BL/6J female mice were randomized to receive vehicle or GH-V (2, 5 mg/kg per day) via injection or osmotic pump for 6 days. In both animal studies body weight and food intakes were recorded regularly. Blood samples and tissue of interest for each independent experiment were collected at different time points. 4) Nested case-control studies: pregnancies associated with inappropriate weight for gestational age, gestational diabetes mellitus (GDM) and pre-eclampsia (PE) were selected from the Screening for Pregnancy Endpoints (SCOPE) study in Auckland, and matched to control cases. Maternal serum samples taken at 20 weeks were assayed for concentrations of GH-V, insulin-like growth factors (IGF-1 & 2) and their major binding proteins (IGFBP-1 & 3) using an enzyme-linked immunosorbent assays (ELISAs) developed in-house. Results: In mouse models, GH-V treatment during pregnancy did not affect maternal body or fetal body weights. However, treatment with 5 mg/kg per day significantly increased maternal fasting plasma insulin concentrations with impaired insulin sensitivity observed at day 18.5. Further, different modes of GH-V delivery had differential effects on growth and metabolism. Compared to continuous treatment, pulsatile GH-V treatment in non-pregnant mice was more effective in stimulating growth but caused marked hyperinsulinemia in mice. In human studies, maternal serum GH-V concentrations in large-for-gestational age (LGA) pregnancies were significantly higher than in appropriate-for-gestational age (AGA) and small-for-gestational age (SGA) pregnancies. Maternal GH-V concentrations at 20 weeks of gestation were positively correlated to birth weight but were not altered in pregnancies complicated by GDM or PE. Conclusions: The findings suggest that maternal GH-V is associated with fetal growth and is a likely mediator of the insulin resistance in pregnancy, implicating a unique role for GH-V in normal and pathological pregnancies.